Roberts Lori M, Woodford Kathleen, Zhou Mei, Black Deborah S, Haggerty Jill E, Tate Emily H, Grindstaff Kent K, Mengesha Wondwessen, Raman Chandrasekaran, Zerangue Noa
Discovery Biology, XenoPort, Inc., 3410 Central Expressway, Santa Clara, California 95051, USA.
Endocrinology. 2008 Dec;149(12):6251-61. doi: 10.1210/en.2008-0378. Epub 2008 Aug 7.
Thyroid hormones require transport across cell membranes to carry out their biological functions. The importance of transport for thyroid hormone signaling was highlighted by the discovery that inactivating mutations in the human monocarboxylate transporter-8 (MCT8) (SLC16A2) cause severe psychomotor retardation due to thyroid hormone deficiency in the central nervous system. It has been reported that Mct8 expression in the mouse brain is restricted to neurons, leading to the model that organic ion transporter polypeptide-14 (OATP14, also known as OATP1C1/SLCO1C1) is the primary thyroid hormone transporter at the blood-brain barrier, whereas MCT8 mediates thyroid hormone uptake into neurons. In contrast to these reports, we report here that in addition to neuronal expression, MCT8 mRNA and protein are expressed in cerebral microvessels in human, mouse, and rat. In addition, OATP14 mRNA and protein are strongly enriched in mouse and rat cerebral microvessels but not in human microvessels. In rat, Mct8 and Oatp14 proteins localize to both the luminal and abluminal microvessel membranes. In human and rodent choroid plexus epithelial cells, MCT8 is concentrated on the epithelial cell apical surface and OATP14 localizes primarily to the basal-lateral surface. Mct8 and Oatp14 expression was also observed in mouse and rat tanycytes, which are thought to form a barrier between hypothalamic blood vessels and brain. These results raise the possibility that reduced thyroid hormone transport across the blood-brain barrier contributes to the neurological deficits observed in affected patients with MCT8 mutations. The high microvessel expression of OATP14 in rodent compared with human brain may contribute to the relatively mild phenotype observed in Mct8-null mice, in contrast to humans lacking functional MCT8.
甲状腺激素需要穿过细胞膜才能发挥其生物学功能。人类单羧酸转运蛋白8（MCT8，即SLC16A2）的失活突变会导致中枢神经系统甲状腺激素缺乏，进而引起严重的精神运动发育迟缓，这一发现凸显了转运对于甲状腺激素信号传导的重要性。据报道，小鼠大脑中的Mct8表达仅限于神经元，由此形成了一种模型，即有机离子转运多肽14（OATP14，也称为OATP1C1/SLCO1C1）是血脑屏障处的主要甲状腺激素转运蛋白，而MCT8介导甲状腺激素进入神经元。与这些报道不同，我们在此报告，除了神经元表达外，MCT8 mRNA和蛋白在人、小鼠和大鼠的脑微血管中也有表达。此外，OATP14 mRNA和蛋白在小鼠和大鼠的脑微血管中高度富集，但在人类微血管中则不然。在大鼠中，Mct8和Oatp14蛋白定位于微血管腔面膜和腔外膜。在人和啮齿动物脉络丛上皮细胞中，MCT8集中在上皮细胞顶表面，而OATP14主要定位于基底外侧表面。在小鼠和大鼠的室管膜细胞中也观察到了Mct8和Oatp14的表达，这些细胞被认为在丘脑下部血管和脑之间形成了一道屏障。这些结果增加了一种可能性，即血脑屏障处甲状腺激素转运减少导致了MCT8突变患者出现的神经功能缺损。与人类大脑相比，啮齿动物大脑中OATP14在微血管中的高表达可能导致了Mct8基因敲除小鼠出现相对较轻的表型，这与缺乏功能性MCT8的人类形成了对比。
